The long-term objective of this project is to identify and characterize the molecular mechanisms that control the onset of meiosis during germline development. Meiosis occurs in the germ cells of every sexually reproducing organism; improper regulation of meiosis in humans can lead to reproductive dysfunction. This proposal focuses on the molecular mechanisms that regulate meiotic entry in the C. elegans germ line, a system amenable to genetic and molecular analyses. Previous work of others has shown that the GLP-1 receptor, a member of the conserved LIN-12/Notch family of intercellular receptors, is central to the mitosis/meiosis decision. Alteration of LIN-12/Notch-mediated signaling has been implicated in human disease. In C. elegans, activation of the GLP-1 receptor in the distal germ line establishes a germline stem-cell population. During development, GLP-1 must be down-regulated at the opposite end of the gonad arm, the proximal germ line, to ensure that meiotic entry occurs in the proximal-most position - otherwise sterility results. The mechanisms that govern GLP-1 activity in the proximal germ line, and thus control meiotic entry, are unknown. Mutants that display a proximal proliferation" (Pro) phenotype offer a unique tool to study the proximal regulation of GLP-1-mediated signaling and its influence on the onset of meiosis. The Pro phenotype is a specific spatial rearrangement of germline polarity characterized by inappropriate mitosis of proximal germ cells, without affecting the mitosis/meiosis decision of cells emanating from the stem-cell population in the distal germ line. The specific aims of the proposal are threefold. First, four new Pro mutants will be genetically and phenotypically characterized, and more Pro mutants will be obtained. Second, a complete genetic, phenotypic and molecular characterization of one of the new Pro genes will be undertaken. Third, cell ablation techniques will be used to determine whether regulation of the timing of meiosis depends on signaling' from the proximal somatic gonad.